Dietary supplement combining colostrum and lactoferrin in a mucosal delivery format

ABSTRACT

A dietary supplement for mammalian consumption, and particularly human consumption, for the purpose of stimulating the immune system, inhibiting infection and increasing tissue repair and healing. Comprising colostrum, lactoferrin, and with modified citrus pectin as an optional component, the dietary supplement is administered in ‘mucosal delivery format’: a dosage form that promotes effective absorption through the lining of the oral cavity.

This application claims benefit of provisional application 60,096,697filed Aug. 14, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of natural dietary supplements. Itrelates particularly to dietary supplements that are able to aid theprevention or inhibition of infection, promote immunological stimulationor increase tissue repair or healing. It is directed particularlytowards the supplementation of human diets, and provides for enhancedabsorption of the proteinaceous active ingredients in the oral cavity.

2. Background of the Invention

Nutrition is a critical determinant of immunological competence and ofthe individual's ability to resist infection and physiological stresses.The health of individuals is affected by poor decisions in society'smanagement of new technology over the past five decades. In particular,the routine use of antibiotics, the consumption of processed foods andthe pollution of the environment have resulted in multiple adverseinfluences upon health. Among these may be included the proliferation ofnew strains of bacteria and viruses that are resistant to existingantibiotic and antiviral agents, compromised immune systems resultingfrom chemical pollutants in food, water and air, as well as impairedability to repair tissue and muscle. Additionally, emotional andphysical stresses from employment, family, exercise and the naturaleffects of aging reduce the effectiveness of the immune system andtissue repair processes.

The continuing widespread use of antibiotics in medicine and agriculturereinforces the selective pressures that increase the types and extent ofantibiotic-resistant microbes in the environment, which thensubstantially increases the cost of treating infection. Moreover,administration of antibiotics frequently causes disruption of the normalbacterial flora colonizing the individual's digestive tract, withresults that are particularly undesirable in weakened patients.

The physiological rigors to which an individual's body is exposed in themodern environment, which include the chemical pollutants andantibiotic-resistant microbes discussed above, indicate the advisabilityof boosting the immune system to facilitate the body's abilities toresist and cope with infection, and to assist the natural, self-healingprocesses. Two groups of individuals are particularly susceptible toinfection and the side effects of treatment: young children and theaged. These individuals may respond poorly to physiological orenvironmental challenges because they typically possess immune systemsthat are, in young children and in the aged respectively, immature ordamaged. Consequently, natural stimulation of these individuals' immunesystems is particularly desirable.

3. Description of the Prior Art

Stimulation of the immune system may occur if the appropriate proteinsare absorbed into an individual's bloodstream. Yet these proteins arenot only degraded rapidly by the acidic and enzymatic conditions of thestomach and intestine but they are also expensive to obtain, even in thequantities and formats used for experimental demonstrations: Lonnerdal &Iyer, 1995, Annu. Rev. Nutr., 15: 93-110. Thus attempts to formulate aneffective dietary supplement able to generate and maintain a state ofimmune stimulation in an individual have been unsuccessful.

If the components of a dietary supplement were to possess, in additionto nutritional characteristics, abilities that aid the body's capacityto resist fresh infection, to suppress existing infection or to increasetissue repair and healing, such abilities would naturally proveadvantageous for achieving the general health enhancing purposesoutlined above. As indicated below, those skilled in the art of therespective fields recognize that each of the two proteinaceous productscolostrum and lactoferrin is able to perform beneficial activities ofthis type: see, for example, Wang, et al., 1995, J. Leuk. Biol., 75:865-874, and Burrin et al., 1995, Pediatr. Res., 37: 593-599.

Colostrum is the pre-milk produced immediately after birth before thebreast secretions stabilize into milk. Prime colostrum from cows isobtained within the first six hours after calving and contains more thantwice the milk solids and four times the protein found in milk from thesame cow obtained forty-eight hours later. The concentrations ofdigestive enzymes, immunoglobulins, cytokines, interferons,glycoproteins, proline-rich peptides and vitamins A, D, E and K are allhigher in prime colostrum than in the later breast secretions. Theimmunoglobulin fraction of the prime colostrum provides the newborn withantibodies, lactoferrin and immune enhancers. These components offer thenewborn protection against viruses, bacteria, allergens and toxins,assisting desirable Acidophilus bacteria to start the colonization ofthe newborn's intestine and help prevent the development ofgastrointestinal infection. Proline-rich peptides (e.g. colostrinin) areimmunomodulatory peptide components of colostrum: Janusz and Lisowski,1993, Arch. Immunol. Therap. Experiment., 41: 275-279. Theseproline-rich peptides are regulators of the thymus gland, which in turnproduces T-lymphocytes that neutralize antigens, including infectiousagents such as bacteria and viruses. Colostrum also contains acombination of growth factors that combat disease, reduce infection andenable the newborn to grow healthily and to heal rapidly: see, forexample, Oda et al., 1989, Comp. Biochem. Physiol., 94A: 805-808 and Xuet al., 1994, Biol. Neonate, 66: 280-287. That even healthy adults maybenefit from the administration of colostrum is suggested by studiesshowing that bovine colostrum whey increases serum levels ofinsulin-like growth factor (IGF-I) in athletes undergoing training: Meroet al., 1997, J. Appl. Physiol., 1997, 83: 1144-1151. Colostrum balancesblood sugars during periods of hyperglycemia or hypoglycemia, slowscatabolism and the breakdown of muscle protein, and it stimulates fatutilization.

In sum, prime colostrum contains powerful healing, growth and repairfactors that activate numerous immune, healing, growth and repairsystems and assist in synthesis, retention and repair of muscle, bone,nerve and cartilage. As the body ages, becomes weakened by illness, oris subjected to physical stresses, it produces less and less of thegrowth, healing and repair factors that are needed to overcome illnessand to heal quickly.

Ettinger, U.S. Pat. No. 4,762,822 (expired) describes the use of humancolostrum as a source for extracting ganglioside, with human milk ormammalian brain being alternative sources. As one of several alternativecomponents of young mammals' dietary supplements the extractedganglioside is used to improve mother's milk substitute foods or forreducing the numbers of gastrointestinal disease-producing organisms ina young mammal.

Lactoferrin is a protein that is secreted in milk, tears, mucus andsaliva, and is expressed by white cells at the site of attack bynumerous pathogens. A primary function of lactoferrin is to bind iron atthe molecular level and thereby act as a highly effective antimicrobialagent. Iron is an essential growth factor for virtually every cell andmicroorganism, and free iron promotes the growth of pathogens in theintestines (bacteria, viruses and fungi), permitting invasion of therest of the body through the intestinal walls: Gillon Ward et al., 1996,J. Trauma, Inj. Inf. Critical Care, 41: 356-364. Lactoferrin is releasedby cells to absorb free iron that would otherwise be available tobacteria, viruses and fungi for growth. Unlike synthetic antibiotics, towhich bacteria may develop resistance through mutation, lactoferrinexerts its bacteriostatic effect as long as the bacteria require ironfor growth.

Additionally, lactoferrin is recognized by specific receptors inmammalian tissues to release iron to the body for normal, healthy cellgrowth. Unlike synthetic antibiotics, lactoferrin has the ability tobind iron, transport it and then release the iron specifically to thebody's own cells through cell surface lactoferrin receptors.

Lactoferrin is a multifunctional protein that is expressed in a varietyof cell types under different mechanisms of control. It has beendemonstrated that lactoferrin plays a central role in the inflammatorydefense processes. Released in abundant quantities by neutrophilsattracted to the site of an invasion, lactoferrin binds the iron madeavailable by serum and damaged erythrocytes. Monocytes and macrophagesingest the iron-saturated lactoferrin, which has also been implicated inthe production of metastable oxygen metabolites associated withbacterial destruction within these blood cells: Wang, et al., 1995, J.Leuk. Biol., 75: 865-874. Lactoferrin also regulates the release oftumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in vivo:Machniki et al, 1993, Int. J. Exp. Path. 74: 433-439.

Due to the iron absorption and release functions of this protein,lactoferrin is the body's primary regulator of iron, a majorbio-regulator of the digestive tract and a natural bacteriostatic agenthaving indirect but broad antibiotic effects. Yet the cost andavailability of human lactoferrin, purified from human breast milk,restricts its use to research.

Lactoferrin's iron-binding bacteriostatic effect, coupled with itsgeneral abundance in breast milk, has led to numerous studies innew-born mammalian offspring, prompting its incorporation into Japanesebaby formula since approximately 1993. Lactoferrin B is an aminoterminal peptide of bovine lactoferrin generated by pepsin digestion andhas been shown to have a potent bacteriocidal activity against a diverserange of potentially pathogenic bacteria: Bellamy et al, 1992, J.Applied Bacteriol., 73: 472-479. The importance of lactoferrin innewborn humans for ensuring the appropriate formation and development ofthe gastrointestinal tract, its bacterial colonization and to enablenutrients to be absorbed effectively, has also been demonstrated.

Many of these functions of lactoferrin are reviewed by Lonnerdal & Iyer,1995, Annu. Rev. Nutr., 15: 93-110. Yet these authors note that therelative efficacy of using either lactoferrin from other species, orrecombinant human lactoferrin for treatment of humans is unproven. Thisis because adequate quantities of human lactoferrin have not beenisolated to supply clinical studies, and recombinant human lactoferrinwill not accurately reproduce the protein's glycan composition.

Tanaka et al., U.S. Pat. Nos. 5,098,722 and 5,008,120 disclose methodsof preparing iron-fortified beverages that contain a solution ofpurified bovine lactoferrin and provide high bio-availability of iron.

Tomita et al., U.S. Pat. No. 5,304,633 disclose fragments of milklactoferrin having potent antimicrobial activity. Kunio et al., U.S.Pat. No. 5,576,299 disclose the use of lactoferrin for preventing andtreating the opportunistic infections that arise in immuno-compromisedindividuals. Yamamoto et al., U.S. Pat. No. 5,725,864 disclose the useof an iron-binding protein, of which lactoferrin is one of severalexamples, for inhibiting infection or suppressing growth of humanimmunodeficiency virus: the protein is administered by diffusion throughany of several epithelial membranes, or by injection. Valenti &Antonini, U.S. Pat. No. 5,834,424 disclose the use of compositionscontaining lactoferrin or other iron-binding proteins for treatingGram-positive bacterial infections.

Nichols & McKee, U.S. Pat. No. 4,977,137 describe the use of milklactoferrin from human and other mammalian sources as a dietaryingredient or supplement. The lactoferrin promoted growth of thegastrointestinal tract of human infants or non-human animals immediatelyon birth. Konig et al., U.S. Pat. No. 5,466,669 disclose animmunostimulatory agent comprising a peptide derived from lactoferrin.

Headon et al., 1990, PCT/US90/02356, European Pat. No. 0 471 011 B1,disclose the verified cDNA sequence of human lactoferrin. Kruzel, 1991,PCT/US91/01335 discloses human lactoferrin expressed from recombinantDNA, its method of production and purification and its use forsupplementing the diet with trace elements or as a topical antiseptic.Kruzel et al., 1995, PCT/US95/05653 disclose the cloning, expression anduses of recombinant human lactoferrin for retarding food spoilage, as atopical antiseptic, for inhibiting microbial growth in or on a mammal,for regulating iron levels within a mammal or for a nutritionalsupplement.

Citrus pectin obtained from citrus peel is modified by a standardtechnique involving limited proteolysis, facilitating passage into thebloodstream of the smaller polypeptide products. Galactose residueslocated on the surface of both the original pectin glycoprotein and themore soluble polypeptide products bind lectins, including cell surfaceproteins of some cancer cells: Raloff, 1995, Science News, 14: 134.Modified citrus pectin consumed in drinking water has been shown to haltthe spread of prostate cancer cells: Pienta et al., 1995, J. Nat'l.Cancer Inst., 87: 348-353.

See, U.S. Pat. No. 5,747,464 discloses the use of apple pectin boundirreversibly to β-sitosterol in a composition which is used as a dietarysupplement for inhibiting absorption of fat and cholesterol from thegut.

The strongly acidic conditions of the stomach, and the function of theproteolytic enzymes and zymogens produced in the pancreas and acting inthe intestines, are well known to inactivate and degrade the delicatestructures of proteins, such as the components of the dietarysupplements described here. As reviewed by Lonnerdal & Iyer, 1995, Annu.Rev. Nutr., 15: 93-110, the species-specific glycosylation oflactoferrins from different mammalian sources may provide protectionfrom proteolysis for lactoferrin ingested naturally from maternal milk,and cross-species administration of lactoferrin would be expected to befar less effective. Even if the lactoferrin succeeds in reaching thesmall intestine intact, specific lactoferrin receptors enable humanlactoferrin to deliver iron to the mucosal cells of human smallintestine, whereas bovine lactoferrin is incapable of doing so: Cox etal., 1979, Biochim. Biophys. Acta, 558: 129-141.

In spite of the knowledge of the beneficial properties of eithercolostrum or lactoferrin when used individually, there remains acontinuing need for an economical dietary supplement to boost the body'sown defense and repair systems and to provide for increased energy,stamina, resilience and tissue repair. The components of the supplementmust be obtainable from economic and abundant sources, yet remaineffective for administration to humans, and preferably to a broad rangeof recipient mammals. Moreover, such a dietary supplement must beabsorbed effectively, without the degradation of protein constituentsthat is associated with regular digestive processes such as thedestruction of delicate immunoglobulins by acids in the stomach.

The oral cavity contains a plethora of mechanisms to counter thesurvival of infectious agents that enter through the mouth and nose:secreted with the saliva are broad-spectrum IgA antibodies, lysozyme andsmall quantities of lactoferrin, and lymphoid cells enter the oralcavity through the gingiva. In addition, it has recently been recognizedthat external factors may also deliver signals that modulate immuneresponses: these factors include cytokines such as the interferons, aswell as hormones, growth factors and cellular antigens.

Studies aimed at preventing allergic inflammation in rodents haveindicated that administration of interferon to mice by oral feedingcould be as effective as intraperitoneal injection. Thus oraladministration of either antigens or cytokines may be capable ofmodulating a variety of physiological reactions, including immuneresponses. Possible routes of mediation are: (a) taste buds of thetongue, connected by nerves to hypothalamus collateral centres, controlappetite and energy utilization; (b) a spectrum of mucosal and secretorycell types present in the oral cavity that are capable of responding tocytokine or antigen signals and releasing further cytokine messages; (c)epithelial cells of the oral cavity, which are likely to be the naturalrecipients of signals entering the mammalian mouth: in the adult thesewould be primarily signals from antigens, whereas for the neonatalmammal important signals would also be received from ingested maternalcytokines and maternal hormones; (d) the submucosal tissue of the oralcavity, which secretes immunoglobulin IgA. Small amounts of eithercytokine or antigen may be recognized as antigen by a responsive cell,resulting in immune activation via initiation of the cytokine cascade,whereas large doses or extended administration may induce tolerance:studies have shown that interferon administered in large doses to humansmay be less effective than minimal quantities. Thus the response willfrequently be individual or case dependent and may be stronglyinfluenced by additional physiological or environmental factors.

The implications of these immunological studies have been reviewedrecently (Georgiades, 1998, Biotherapy, 11: 39-51) with the conclusionthat the tolerance phenomenon is not only limited to the oraladministration of antigen but may occur when immunization is attemptedvia any mucosal membrane, such as the nasal tract. In the light of suchconflicting results and controversial hypotheses it could be consideredcounter-intuitive, and certainly unpredictable, to attempt to stimulateor potentiate an immune response by administering cytokinins andimmunoglobins orally by means of a combination of prime colostrum andlactoferrin.

4. Objects of the Invention

The invention addresses the requirement for an effective and economicaldietary supplement comprising one or more natural stimulators of immunefunction, prevention of and protection from infection, and improvedtissue repair and healing. Furthermore, this supplement must be providedin a convenient format that permits absorption of the active componentsinto an individual's bloodstream in a manner that avoids the body'snormal digestive mechanisms. The present invention emphasizes theefficacy of oral administration of the dietary supplement and promotionof the supplement's efficient absorption through the oral cavity'sepithelial lining by presenting the supplement in a ‘mucosal deliveryformat’ (MDF). Those MDFs of the invention that are preferred, e.g.chewable lozenges, also render the dietary supplement of the inventionparticularly adaptable to self-monitored dosages, and are especiallyappropriate for regimes of self administration.

SUMMARY OF THE INVENTION

The present invention encompasses dietary supplements containinglactoferrin and colostrum in combination, thus providing an improvementover previous supplements which lacked one or other or both of thesecomponents. When absorbed in combination the effects of colostrum andlactoferrin on the health and well-being of the recipient aresurprisingly beneficial, being greater than would be anticipated fromthe known properties of each component taken in isolation and includingthe promotion of resistance to infection, stimulation of immune functionand the increase of tissue repair and healing. Absorption of thecomponents in the oral cavity, rather than through the lining of eitherthe stomach or intestine is particularly efficacious: hence theinvention includes the provision of the components in a mucosal deliveryformat, or ‘MDF’, such as a chewable lozenge.

The present invention provides a dietary supplement containinglactoferrin and colostrum, which may also contain modified citruspectin. It also provides a composition containing these ingredientswhich may also include nutritionally acceptable carriers, diluents andflavorings, a method of administering such a composition in a formappropriate for absorption through the lining of the oral cavity, and amethod of promoting resistance to infection, stimulation of immunefunction and an increase of tissue repair and healing.

Thus a mucosal delivery format that combines lactoferrin with primecolostrum boosts the body's defense, growth, healing and repair systems,enhances immune system function, and binds excess free iron. Thisresults in increased energy and stamina, accelerated tissue repair andimproved resilience to infection. Providing the dietary supplement inthe form of lozenges which may be dissolved slowly in the mouth permitsthe lactoferrin and colostrum to achieve their optimal effects: toenergize the immune system to build the body's own disease defensesnaturally, to keep pathogens in check and to help the body repair vitaltissue. The inclusion of modified citrus pectin as a component of thedietary supplement offers the potential for providing protection fromthe spread of certain cancers. Taking one of the lozenges of theinvention once or twice or more often per day, as needed, provides thesuggested dietary supplement. Immuno-compromised individuals, diabetics(particularly ‘brittle diabetics’) and the elderly can benefit fromlarger doses of lozenges.

DETAILED DESCRIPTION OF THE INVENTION

The invention has been found effective for numerous physiologicaldisorders caused by and resulting in a variety of metabolic insults,including routine antibiotic use, toxic pollutants, processed foods,stress, aging and impaired muscle repair.

The invention encompasses compositions, dietary supplements and methodsfor their use that include the following active components:

(a) Prime colostrum has the highest concentrations of immunoglobulins,interferons, proline-rich peptides, amino acids and vital enzymesproduced by mammary tissue, being higher than those produced in ordinarycolostrum. This provides the newborn with protection against viruses andbacteria and other health threats. Besides providing the first completefood for the newborn, prime colostrum has profound immuno-stimulatingproperties: administration of very small amounts activates the humanimmune system. In addition to this immune stimulation capability, primecolostrum provides immunoglobulins directly (e.g. IgA, IgG, IgM) andalso growth factors (e.g. IGF-I, TGF A and B). It suppliesimmunomodulatory proline-rich peptides which moderate the activity ofthe immune system through their effect upon the thymus gland,stimulating under-active immune systems such as those ofimmuno-compromised persons, or moderating those that are over-active asin individuals with auto-immune diseases. Prime colostrum slows musclebreakdown, improves protein synthesis and utilization, providesdigestive enzymes, regulates blood sugar and stimulates growth andrepair. In sum, prime colostrum contains powerful healing, growth andrepair factors that activate numerous immune, healing, growth and repairsystems and assist in synthesis, retention and repair of muscle, bone,nerve and cartilage. As the body ages, becomes weakened by illness, oris subjected to physical stresses, it produces less and less of thefactors that are needed to overcome metabolic insults or infection andto heal quickly.

(b) Lactoferrin is an iron binding protein that occurs naturally in thebody. It is secreted in milk, tears and saliva, and is expressed bywhite blood cells. Lactoferrin is well known in the art as a biologicalregulator that performs many important functions in the body. Thesefunctions include maintaining a healthy balance in the digestive tract,helping the immune system and promoting healthy cell growth. Dairycattle currently provide the only cost-effective source of lactoferrinfor inclusion into a dietary supplement, even though cows' milk containsa relatively low concentration of lactoferrin. Lactoferrin from cows'milk can be prepared free of lactose; it bioregulates iron, boosts theimmune system, balances the digestive tract, increases energy andstamina and promotes cell growth and healing. These broad, beneficialproperties are surprising in view of the inability of bovine lactoferrinto bind to the lactoferrin receptors at the surface of the mucosal cellsof human small intestine.

(c) Modified citrus pectin is an optional component that endows thecomposition with additional benefits as a nutritional supplement. Citruspectin is a protein that contains galactose molecules on its surfacewhich are able to bind lectins involved in the transmission within thebody of certain types of cancer. Modified citrus pectin has been treatedto reduce its molecular size, thereby increasing its solubility andability to be absorbed into the bloodstream.

(d) Citric acid is a further optional component that may be incorporatedto promote salivation and to adjust the acidity of the composition inorder that solubility, activity and absorption of the components withinthe oral cavity is enhanced.

Iron is a key mineral required by all microorganisms for maintenance andgrowth. Excess iron in the intestines promotes pathogen growth andproliferation. Lactoferrin from cows' milk is partially saturated withiron (approximately 25% of total saturation) providing a dietary sourceof iron as well as a means of scavenging free iron from the oral cavityand digestive tract. Lactoferrin works on contact to starve pathogens ofiron so that the correct balance of beneficial bacteria develops and ismaintained in the digestive tract; the growth of harmful bacteria thatare poorly adapted to these conditions being inhibited. By sequesteringiron and delivering it for use by the cells of the body's internaltissues lactoferrin improves digestion and boosts the body's naturaldefense mechanisms. This generates more energy and increased stamina forphysical activities and optimum health.

Lactoferrin and prime colostrum achieve their optimal effects whendissolved slowly in the mouth, rather than being swallowed directly inthe form of a pill or capsule. Slowly dissolving the lactoferrin andconstituents of colostrum in the mouth permits their absorption into thecapillaries at the surface of the oral cavity's lining, and this is ableto occur before the lactoferrin and prime colostrum are exposed to theharsh degradatory conditions of the stomach and intestines. For example,bovine lactoferrin is less resistant to degradation in the humandigestive tract than is human lactoferrin, and the lactoferrin receptorsin the small intestine of humans will not bind bovine lactoferrin. Thusadministration of bovine lactoferrin to humans in a mucosal deliveryformat, such as a format that enables its absorption through the liningof the mouth, is particularly efficacious. Immunoglobulins fromcolostrum also pass directly into the blood through the inner mucosallayer of the mouth. Prime colostrum is capable of energizing the immunesystem when the appropriate dose is slowly absorbed by the body: aslittle as 125 mg of prime colostrum in the oral cavity will trigger animmune response event. Orally delivered prime colostrum stimulates thebody to replace growth, healing and repair factors as needed and producethem naturally to achieve homeostasis. Oral administration of modifiedcitrus pectin has been shown to be effective for inhibiting spontaneousmetastasis of a rat prostate cancer.

Lozenges, in contrast to pills or capsules, provide a ‘mucosal deliveryformat’ (MDF) for constituents which can be absorbed through the oralmucosal surface, such as the colostrum, lactoferrin or modified citruspectin of the invention. In particular, the lozenges of the inventionare able to enhance the benefits associated with absorption ofappropriate constituents through the oral epithelial mucosa and into theunderlying lymphatic system, for they are designed to be dissolvedslowly in the mouth and they may also be chewable: such lozenges aretherefore a preferred MDF. By using a cold-pressing technique tomanufacture the lozenges heat degradation of sensitive biologicalcomponents is minimized. Lozenges are also preferable to hard-pressedtablets or capsules for the latter do not dissolve until exposed to thegastric juices of the stomach. These strongly acidic juices degrade theinterferon, the other immuno-stimulating proteins and immunoglobulinsthat are contained in colostrum. Similarly, oral administration usinglozenges as the mucosal delivery format, but not capsules or hardtablets, allows the lactoferrin to sequester iron in the upper digestivetract and thereby broaden the effect of its bacteriostatic actions.

The present invention, in common with many dietary supplements,incorporates ingredients derived from dairy sources. Dairy productsgenerally contain sufficient lactose to prevent lactose-intolerantindividuals from using them in their diets. Ingestion of 77 mg lactosecan be sufficient to create an adverse response in a lactose-intolerantindividual. The present invention uses highly purified products,including lactose-free lactoferrin and prime colostrum that contains nomore than 10% lactose. This enables lactose levels to be maintained ator below 75 mg lactose per individual dosage so that adverse responseswill be avoided while incorporating prime colostrum at up to 750 mg.Also, the use of prime colostrum itself provides an advantage in thisregard, as its ratio of beneficial protein to lactose is greater than inregular colostrum.

In its first feeding, a new-born calf ingests prime colostrum, whichitself contains lactoferrin. However, the proportion of theseingredients is very different to that in the dietary supplement of theinvention. The initial one-half liter liquid colostrum provided by a cowprovides 110 g dry weight prime colostrum, including 55 mg lactoferrin(a ratio of 2000:1). As described in the Examples, the typical dosageunit of the invention provides 150 mg prime colostrum and 10 mglactoferrin (a ratio of 15:1), delivered to a mammal of comparable size.Yet the beneficial effects of the invention are observed in spite ofthese ingredients being delivered in far smaller quantities (severalorders of magnitude in the case of the colostrum component). Thus theinvention serves as a true dietary supplement, requiring combination ofthe ingredients in an unpredictable proportion.

Given the species-specificity of human intestinal lactoferrin receptorsand the apparent ease with which antigenic tolerance can be induced in avariety of mammals from rodents to primates, the efficacy of theinvention in achieving its stated aims is remarkable. By administeringthe combination of bovine prime colostrum and bovine lactoferrin notonly are beneficial effects of each component observed, but asynergistic effect is apparent: the results of combined administrationare greater than may be accounted for by an additive effect of theindividual components. The results observed, and described below in theExamples, may stem not only from the novel combination of ingredients,but also from the manner in which they are administered and the apparentinducement of immunological responses that is possible when suchmaterials are provided in the recommended doses and allowed to beabsorbed through the epithelial lining of the oral cavity.

The individual components of the composition may be obtained fromcommercial sources: colostrum (which is dehydrated by standardspray-drying procedures known in the art) from any processing facilityapproved by the United States Food and Drug Authority (F.D.A.) such asImmuno-Dynamics, Inc. of Perry Iowa, U.S.A.; lactoferrin from approvedmanufacturers such as DMV International Nutritionals of Frazier N.Y.,U.S.A.; modified citrus pectin from approved distributors ormanufacturers such as G.C.I. of Los Angeles Calif., U.S.A.; flavors fromapproved distributors or manufacturers such as Allen Flavors, Inc. ofEdison N.J., U.S.A. Manufacturing of the composition, the dietarysupplement, and the oral dosage forms may each be performed usingstandard techniques appropriate for the food or pharmaceuticalindustries, as at F.D.A. approved facilities such as Summa RxLaboratories, Inc. of Mineral Wells Tex., U.S.A.

1. Description of Presently Preferred Embodiments

A preferred embodiment of the invention is a composition for use as adietary supplement for a mammal, comprising nutritionally effectiveamounts of colostrum and of the protein lactoferrin, sufficient topromote an effect in the mammal that is selected from: resistance tofresh infection, suppression of existing infection, stimulation ofimmune function, and the increase of tissue repair and healing. Aparticularly preferred embodiment is such a composition for use as adietary supplement for humans.

Preferred embodiments of the invention comprise such a composition inwhich the lactoferrin is present at a concentration of from about 10 mgto about 100 mg per 1500 mg total weight and the colostrum is dehydratedcolostrum, prepared by a mechanism such as spray drying, and present ata concentration of from about 125 mg to about 1250 mg per 1500 mg totalweight. In such a preferred embodiment a 1500 mg dose is typicallyprovided from one to about five times per day. Supplementary doses maybe warranted under particular nutritional or physiological conditions.Additional preferred embodiments include such compositions for use as adietary supplement that additionally comprise modified citrus pectin ata concentration of from about 1.5 mg to about 15 mg per dose.

Further preferred embodiments include such compositions, with or withoutmodified citrus pectin, in which the lactoferrin is obtained from milk,particularly bovine milk, and also where the colostrum is primecolostrum, especially that from bovine sources. In any of theseembodiments the composition may further comprise nutritionallyacceptable carriers, adjuvants or diluents as are known in the art.Advantages of incorporating such additional components includestabilization of the composition for easier or more effectivepreparation, distribution or administration, improvement of theeffectiveness of delivering the active components once administered and,as described below for fillers, sweeteners and flavors, to increase theattractiveness of the composition as an edible product.

Another preferred embodiment of the invention is a dietary supplementfor promoting in mammals, especially humans, an effect of resistance tofresh infection, suppressing existing infection, stimulating immunefunction, or increasing tissue repair and healing; wherein the dietarysupplement comprises the composition that includes nutritionallyeffective amounts of colostrum and of the protein lactoferrin and mayadditionally include modified citrus pectin. Preferred sources, types,methods of preparation and concentration ranges for these components areas indicated above. The dietary supplement is preferably prepared in a‘mucosal delivery format’; particularly as an oral dosage form thatpromotes absorption of the dietary supplement's components within theoral cavity. Such forms are described in greater detail below.

An additional preferred embodiment of the invention is a method ofpromoting in mammals an effect of resistance to fresh infection,suppressing existing infection, stimulating immune function, orincreasing tissue repair and healing: the method comprises theadministration of an effective amount of dietary supplement containingthe composition that includes nutritionally effective amounts ofcolostrum and of the protein lactoferrin. The composition mayadditionally include modified citrus pectin. An especially preferredembodiment is that in which the mammal is human. Preferred embodimentsinclude methods in which the sources, types, methods of preparation andconcentration ranges of the components of the composition are asdescribed above. Other preferred embodiments include those in which thedietary supplement is prepared in a ‘mucosal delivery format’;particularly as an oral dosage form to promote absorption in the oralcavity, as indicated above.

Further preferred embodiments of the invention include compositions,dietary supplements and methods, as described above, in which thecomposition contains one or more of the following components: citricacid, dextrose and/or sucrose as filler and sweetener, artificial ornatural flavors such as fruit or vanilla or chocolate flavoring, plussilicon dioxide and/or magnesium stearate as a physical binder tofacilitate mechanical handling during preparation and packaging.

Preferred embodiments of the invention include compositions and dietarysupplements, as described above, prepared in a ‘mucosal deliveryformat’; particularly as an oral dosage form that promotes absorption ofthe dietary supplement's components through the epithelial lining of theoral cavity. Further preferred embodiments are methods for promotingthose beneficial effects in mammals described above, in which such oraldosage forms of these compositions and dietary supplements areadministered. Examples of oral dosage forms that promote absorption ofthe dietary supplement's components within the oral cavity are thosethat encourage retention of the dose within the oral cavity for anextended period, or discourage swallowing of the dose. Dosage forms thatare chewable or that are appropriate for sucking are examples; they maybe additionally designed to encourage salivation. Such dosage formsinclude lozenges, particularly chewable lozenges, chewable tablets andchewable gums. The addition of natural or artificial flavoring alsoencourages retention of the dosage form within the mouth, particularlywith children, so that there is greater transfer of the activecomponents through the lining of the oral cavity and into thebloodstream and/or the lymphatic system. Such active components includethe constituents of colostrum and the lactoferrin, as described above.The physical size and consistency of the dosage form may also be adaptedto prevent premature swallowing of the delivered dose; 30 seconds to tenminutes is the recommended period for which the dose should remain inthe mouth for effective absorption, with better effects being observedat the longer retention times. Larger chewable forms are appropriate foranimals that would otherwise be likely to swallow such foodstuff withlittle mastication.

In the currently most preferred embodiment of the invention thecomposition comprises the following ingredients cold pressed into achewable lozenge of hardness 14 to 44 Kp that is taken as a nutritionalsupplement one to five times per day: 150 mg to 200 mg bovine primecolostrum, 10 mg to 20 mg bovine lactoferrin, 5 mg modified citruspectin, 1295 mg to 1945 mg dextrose, 7.5 mg to 12.0 mg citric acid, 4.5to 15.0 mg natural and/or artificial flavor (to taste), 7.5 mg silicondioxide, 7.5 mg magnesium stearate and dextrose to a total weight of 0.5to 3.0 grams. The lozenge is chewed for 30 seconds to ten minutes tomaximize absorption of the active ingredients through the lining of theoral cavity and their absorption into the blood and lymphatic system.

2. Working Examples

In order to illustrate the nature of the invention more fully, and themanner in which it is to be practiced, the following examples arepresented:

EXAMPLE 1

Product ‘CLP’: each of the following ingredients is placed, in powderedform, into a commercial mixer: 150 parts bovine prime colostrum, 10parts bovine lactoferrin, 5 parts modified citrus pectin, 1297.5 partsdextrose, 7.5 parts citric acid, 15 parts natural strawberry flavor, 7.5parts silicon dioxide and 7.5 parts magnesium stearate. If necessary thematerials are passed through a #10-12 mesh screen to remove aggregates.Each of the procedures should be performed with precautions againstexposure to the powders and dusts that are formed, and particularlyagainst their inhalation. After 20 minutes of thorough mixing coldpressing the composition in a tablet press set at a maximum pressure of6.4 tons yielded lozenges of weight 1500 mg and hardness 34 to 36 Kp.

EXAMPLE 2

Product ‘IGF 2020’: each of the following ingredients is placed, inpowdered form, into a commercial mixer following the same procedure asfor Example 1: 200 parts bovine prime colostrum, 20 parts bovinelactoferrin, 5 parts modified citrus pectin, 1943.5 parts dextrose, 12parts citric acid, 3 parts natural strawberry flavor, 1.5 partsartificial flavor (e.g. vanilla, chocolate) 7.5 parts silicon dioxideand 7.5 parts magnesium stearate. After mixing and cold pressing as inExample 1, lozenges of weight 200 mg were formed which demonstrated ahardness of 34 to 36 Kp.

EXAMPLE 3

Product ‘IGF 2020-J’: each of the following ingredients is placed, inpowdered form, into a commercial mixer following the same procedure asfor Example 1: 200 parts bovine prime colostrum, 20 parts bovinelactoferrin, 5 parts modified citrus pectin, approximately 215 partsdextrose and/or maltodextrin, approximately 10 parts stearic acid asbinder. After mixing and cold pressing as in Example 1, lozenges oftotal weight 400 mg to 600 mg were formed.

EXAMPLE 4

Product ‘CLP’ (Example 1) was self-administered by subject A, an adultwoman with a long history of gastrointestinal disorders, includingirritable bowel syndrome. Over several years subject A had experiencedno relief from medications prescribed by physicians. Colon symptomsimproved as soon as a regime was initiated in which four to fivelozenges of product ‘CLP’ (Example 1) were dissolved slowly in the mouthdaily. Over three months the irritable bowel syndrome improved to thepoint at which symptoms were absent.

EXAMPLE 5

Product ‘CLP’ (Example 1) was self-administered by Subject B, an adultman with a history of medical disorders following exposure to toxicdefoliants. The subject has suffered from pancreatic failure and hadbeen insulin dependent as a ‘brittle diabetic’ for twenty years, losingthe sight in one eye during this time. After two months under a regimeof two lozenges of product ‘CLP’ daily, the subject was able to halvehis daily dosage of insulin, while observing over the same periodimproved healing of bruises and cuts, elimination of the splitting offingernails and toenails, and noting an accompanying increase in energylevel and alertness.

EXAMPLE 6

Product ‘CLP’ (Example 1) was self-administered by subject C, an adultmale. At age 42, after an eighteen-month regime averaging three lozengesper day the subject's concentration of IGF-I (insulin-like growthfactor-I) in the bloodstream was 393 ng ml⁻¹. This value is 175% of themedian of the normal range for males of 40 to 54 years of age (90 to 360ng ml⁻¹) and 9.2% higher than the upper limit of this range.

Clinical methods to measure IGF-I blood concentration are well known. Inmuscle IGF-I has several metabolic effects including the stimulation ofglucose metabolism, increased uptake of nutrients, enhancement of cellproliferation and inhibition of protein degradation (Dohm et al., 1990,Diabetes, 39: 1028-1030; Tollefsen et al., 1989, J. Biol. Chem., 264:13810-13817). Thus levels of IGF-I in the blood indicate metabolicpotential for healing and growth, which may reflect immune systemactivity. While the concentration of IGF-I circulating within the bloodlies within a broad range for a population of subjects, a smallvariation in the concentration in a particular individual's blood canindicate a significant change in immunological stimulation. Thus theobservation is indicative of a long-term beneficial effect of thedietary supplement of the invention.

EXAMPLE 7

Product ‘IGF 2020’ (Example 2) was self-administered by subject D, anadult male aged 30 years. Over a seven day regime of one lozenge per daythe concentration of IGF-I in the blood of subject D rose 9.1%, from 265ng ml⁻¹ to 289 ng ml⁻¹. This indicates a short-term beneficial effect ofthe dietary supplement of the invention.

EXAMPLE 8

Product ‘CLP’ (Example 1) was administered daily to Subject E, anelderly canine exhibiting, among other symptoms, intestinal bleeding.Contrary to the veterinary prognosis of rapid deterioration and deathwithin days or weeks, evidence of the bleeding has ceased and Subject Ehas continued to survive for longer than six months.

It should be understood that the foregoing disclosure emphasizes certainspecific embodiments of the invention and that all modifications oralternatives equivalent thereto are within the spirit and scope of theinvention as set forth in the appended claims.

What is claimed is:
 1. A composition for use as a human dietarysupplement, the composition comprising lactoferrin, dehydratedcolostrum, and modified citrus pectin, prepared as a lozenge, a chewablelozenge, a chewable tablet, or a chewable gum.
 2. The composition ofclaim 1, wherein the composition promotes an effect in the humanselected from resistance to fresh infection, suppression of existinginfection, stimulation of immune function, and the increase of tissuerepair and healing.
 3. The composition of claim 1, wherein thelactoferrin is bovine milk lactoferrin.
 4. The composition of claim 1,wherein the lactoferrin is present at a concentration of from about 10mg per 1500 mg total weight of the composition to about 100 mg per 1500mg total weight of the composition.
 5. The composition of claim 1,wherein the dehydrated colostrum is present at a concentration of fromabout 125 mg per 1500 mg total weight of the composition to about 1250mg per 1500 mg total weight of the composition.
 6. The composition ofclaim 1, wherein the modified citrus pectin is present at aconcentration of from about 1.5 mg per 1500 mg total weight of thecomposition to about 15 mg per 1500 mg total weight of the composition.7. The composition of claim 1, wherein: the lactoferrin is present at aconcentration of from about 10 mg per 1500 mg total weight of thecomposition to about 100 mg per 1500 mg total weight of the composition;and the dehydrated colostrum is present at a concentration of from about125 mg per 1500 mg total weight of the composition to about 1250 mg per1500 mg total weight of the composition.
 8. The composition of claim 1,wherein: the lactoferrin is present at a concentration of from about 10mg per 1500 mg total weight of the composition to about 100 mg per 1500mg total weight of the composition; the dehydrated colostrum is presentat a concentration of from about 125 mg per 1500 mg total weight of thecomposition to about 1250 mg per 1500 mg total weight of thecomposition; and the modified citrus pectin is present at aconcentration of from about 1.5 mg per 1500 mg total weight of thecomposition to about 15 mg per 1500 mg total weight of the composition.9. The composition of claim 1, further comprising nutritionallyacceptable carriers, diluents, or flavorings.
 10. The composition ofclaim 1, prepared as an oral dosage form that promotes absorption of thedietary supplement's components within the oral cavity.
 11. Thecomposition of claim 1, wherein the lactoferrin is bovine milklactoferrin.
 12. The composition of claim 1, wherein the composition issolid.